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EP2121785B1 - Sydnoniminspezifische dopamin-wiederaufnahmehemmer und ihre verwendung zur behandlung von dopaminbedingten erkrankungen - Google Patents

Sydnoniminspezifische dopamin-wiederaufnahmehemmer und ihre verwendung zur behandlung von dopaminbedingten erkrankungen Download PDF

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EP2121785B1
EP2121785B1 EP08732213.7A EP08732213A EP2121785B1 EP 2121785 B1 EP2121785 B1 EP 2121785B1 EP 08732213 A EP08732213 A EP 08732213A EP 2121785 B1 EP2121785 B1 EP 2121785B1
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compound
treatment
sydnonimine
phenylcarbamoyl
disorders
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EP2121785A4 (de
EP2121785A1 (de
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Hao Chen
Ming Liu
Qi Su
Manish Raisinghani
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Caliper Life Sciences Inc
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Caliper Life Sciences Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/04—1,2,3-Oxadiazoles; Hydrogenated 1,2,3-oxadiazoles
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to certain Sydnonimine derivatives that bind specifically to dopamine transporter (DAT) proteins or the site of dopamine reuptake, compositions comprising same, and the use of such derivatives for treating, or delaying the progression of, various disorders and illnesses alleviated by inhibiting dopamine reuptake.
  • DAT dopamine transporter
  • Neurotransmitters are chemical "messengers" that function to relay electrical signals across the gap or synaptic cleft between one neuron, or nerve cell, and another. Neurotransmitters are stored in tiny sacs called vesicles, located at nerve endings. As an electrical signal arrives at a neuron's terminal, the vesicles move to the neural membrane and releases their neurotransmitter molecules into the synaptic cleft. The neurotransmitters formed in the pre-synaptic (or sending) neuron diffuse across the gap and lock onto binding sites or receptors on the membrane of a neighboring, post-synaptic (or receiving) neuron.
  • Dopamine is a type of neurotransmitter that is formed in the brain and effects the processes that regulate movement, motivation, emotional response and the capacity to feel pleasure and pain. Dopamine is vital for performing balanced and controlled movements. After dopamine becomes bound to a receptor in the process of transmitting nerve signals, it is eventually released and removed from the synaptic cleft, back into the pre-synaptic neuron or glial cell by a reuptake process which operates under the influence of a protein, known as dopamine transporter (DAT), present on the neuron's outer membrane. In other words, the DAT protein acts to clear the dopamine out of the synaptic cleft, a process which is essential to normal transmission of nerve signals.
  • DAT dopamine transporter
  • DAT protein is a major determinant of the intensity and duration of the dopaminergic signal.
  • Knockout mice lacking the dopamine transporter display marked changes in dopamine homeostasis that result in elevated dopaminergic tone and pronounced locomotor hyperactivity ( Gainetdinov et al. (2001) Proc. Natl. Acad. Sci., 98:11047-54 ; Hall et al. (2003) Neuropsychopharmacology, 28:620-8 ; Mateo et al. (2004) Proc. Natl. Acad. Sci., 101:372-7 ).
  • a number of behavorial disorders and other debilitating illnesses can be alleviated by therapeutic agents that bind to DAT proteins and inhibit dopamine reuptake. These include cocaine addiction, attention deficit disorder, depression, Parkinson's disease, obesity narcolepsy, and schizophrenia, to name a few.
  • DAWN Drug Abuse Warning Network
  • dopamine transporter-selective compounds may be used alone or in combination with clinically available selective serotonin reuptake inhibitors (SSRIs) for treating cocaine abuse and addiction
  • SSRIs selective serotonin reuptake inhibitors
  • mice with no dopamine transporter gene and either one copy or neither copy of the serotonin transporter displayed no preference for places where they had previously received cocaine. That is, without the concurrent reuptake of dopamine and serotonin, the mice are no longer "addicted" to cocaine. It is conceivable the dopamine and serotonin transport systems may have compensated for each other, and that cocaine dependency and reward behavior may be mediated through this redundancy or compensatory mechanism.
  • Imbalances in the dopaminergic system have been implicated as contributing factors in the occurrence of several neuropsychiatric disorders, including attention deficit disorder, depression and certain symptoms of schizophrenia.
  • Attention deficit disorder is a learning disorder involving developmentally inappropriate inattention, with or without hyperactivity.
  • the primary signs of attention deficit disorder are a patient's inattention and impulsivity. Inappropriate inattention causes increased rates of activity or reluctance to participate or respond.
  • a patient suffering from attention deficit disorder exhibits a consistent pattern of inattention and/or hyperactivity-impulsivity that is more frequent and severe than is typically observed in individuals at a comparable level of development.
  • PET positron emission tomography
  • Methylphenidate (Ritalin®) a compound of similar pharmacological profile to cocaine, specifically increases the brain dopamine level, hence exhibiting the phenotypic therapeutic effects.
  • ADHD attention-deficit hyperactivity disorder
  • hyperkinetic disorder hyperkinetic disorder
  • mice lacking the gene encoding the DAT have elevated dopaminergic tone and exhibit marked hyperactive. This activity is exacerbated by exposure to a novel environment. Additionally, these mice were impaired in spatial cognitive function, and they showed a decrease in locomotion in response to psychostimulants. This paradoxical calming effect of psychostimulants depended on serotonergic neurotransmission.
  • the parallels between DAT knockout mice and individuals with ADHD suggest that common mechanisms may underlie some of their behaviors and responses to psychostimulants. Haloperidol has been shown to produce a sedative effect on such mice.
  • Depression is one of the most common of emotional disorders, having a morbidity rate of over 10% in the general population. Depression is characterized by feelings of intense sadness, despair, mental slowing, loss of concentration, pessimistic worry, agitation, and self-deprecation ( Harrison's Principles of Internal Medicine, 2490-2497 (Fauci et al., eds., 14th ed. 1998 )). Depression can have physical manifestations including insomnia, hypersomnia, anorexia, weight loss, overeating, decreased energy, decreased libido, and disruption of normal circadian rhythms of activity, body temperature, and endosine functions. Moreover, as many as 10% to 15% of depressed individuals display suicidal behavior.
  • Schizophrenia is considered by medical professionals to be a thought disorder, mood disorder and anxiety disorder. There is no known cure for schizophrenia. Thus, treatment is directed at the symptoms of schizophrenia and often involves administration of a combination of antipsychotic, antidepressant and antianxiety drugs.
  • Antipsychotic drugs such as haloperidol, have been in use for the treatment of schizophrenia since at least the 1950's. These established drugs act by blocking dopamine receptors and thereby control the hallucinations, delusions and confusion of schizophrenia.
  • newer drugs have been introduced, e.g. quetiapine fumerate, and risperidone, which interact with both the dopamine and serotonin receptors, so as to treat the broad range of schizophrenia's symptoms.
  • One of the principal impediments to the success of treatments for schizophrenia is that patients frequently discontinue prescribed medication(s), especially those having undesirable side effects, such as blurred vision, dizziness, muscle spasms, cramps, tremors and other Parkinson-like symptoms.
  • DAT blockers and genetic "DAT knock-out" mice are both resistant to the negative effects of specific neurotoxins, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) on dopaminergic neurons. Therefore, a pharmacological blockade of DAT protein by potent and selective inhibitors may provide effective therapy by preventing the onset or delaying the progression of Parkinson's disease, and offer symptomatic benefits associated with increases in CNS dopamine levels.
  • MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • 6-OHDA 6-hydroxydopamine
  • Obesity is a disorder characterized by an abnormal increase of fat in the subcutaneous connective tissues.
  • therapeutic agents currently used to treat obesity are those that increase food intake, such as drugs that interfere with monoamine receptors, e.g., serotonin receptors, dopamine receptors, noradrenergic receptors and histamine receptors.
  • Narcolepsy is a neurological disorder marked by a sudden recurrent, uncontrollable compulsion to sleep, also associated with cataplexy (i.e., a sudden loss of muscle tone and paralysis of voluntary muscles associated with a strong emotion), sleep paralysis, hypnagogic hallucinations and automatic behaviors.
  • the disease afflicts all races, females and males alike. It can vary in severity, with symptoms most commonly appearing in a person's teens and early twenties.
  • Narcolepsy is clinically treated using central nervous system (CNS) stimulants, such as Ritalin® which exerts many of its effects through dopamine uptake blockade of central adrenergic neurons, and in particular by blocking DAT proteins.
  • CNS central nervous system
  • Sydnocarb (3-(1-methyl-2-phenylethyl)-N-(phenylcarbomoyl) sydnone imine) has been discovered to have a CNS stimulatory effect, marked by an increase in locomotor activity with practically no peripheral sympathomimetic action, as described in GB Patent 1,262,830 and German Offenlegungsschrift 2028880 .
  • This discovery led to the synthesis of various sydnocarb analogues, which also act as CNS stimulants. See, for example, U.S. Patent Nos. 4,277,609 , 4,301,285 , 4,371,697 and 4,446,322 .
  • sydnocarb also known as mesocarb, and some of its closely related analogues are in fact derivatives of amphetamine, a highly addictive psycho-stimulant.
  • mesocarb When administered to human subjects, it is highly likely that individuals' metabolisms may convert sydnocarb back to amphetamine.
  • sydnocarb may exhibit higher abuse potential than those compounds that are without the propensity to be converted in this way.
  • sydnocarb is listed among the prohibited stimulants in the 2006 Guide to Prohibited Substances and Prohibited Methods of Doping, edition 6, Table 6, at 30, United States Anti-Doping Agency, Colorado Springs, CO (December 2005) (www.usantidoping.org ) .
  • sydnocarb and closely related derivatives are modest reuptake inhibitors. Although having some preferential affinity towards dopamine reuptake proteins, these compounds exhibit affinity toward norepinephrine reuptake transporters, as well.
  • the present invention provides, in one aspect, a compound for use in a method for treatment of or delaying progression of disorders that are alleviated by inhibiting dopamine reuptake, the method involving administering to a patient in need of such treatment a therapeutically effective amount of a compound selected from N-phenylcarbamoyl-3-(p-methyl-benzyl)-sydnonimine and N-phenylcarbamoyl-3-(phenylpropyl)-sydnonimine and the pharmaceutically acceptable salts of said compound.
  • the present invention provides novel Sydnonimine derivatives selected from N-phenylcarbamoyl-3-(p-methyl-benzyl)-sydnonimine and N-phenylcarbamoyl-3-(phenylpropyl)-sydnonimine, and pharmaceutically acceptable salts thereof.
  • the present invention provides pharmaceutical compositions comprising one or more of the sydnonimine derivatives above in combination with a pharmaceutically acceptable carrier medium.
  • the DAT inhibitor compounds described herein differ from sydnocarb, not only in structure, but, more importantly, in their observed effects on animal behavior.
  • sydnocarb is a stimulant, as evidenced by its locomotor stimulating effect in open field studies. J. Witkin et al., J. Pharm. Exptl. Therap., 288(3): 1298-1310 (1999 ).
  • NIDA N-IDA
  • the compounds of the present invention are potent and specific dopamine reuptake inhibitors, having no appreciable affinity towards norepinephrine reuptake proteins. Another advantage of the compounds described herein is that they exhibit no propensity for conversion to amphetamine in vivo.
  • the present invention includes specific compounds defined above, pharmaceutical compositions comprising such compounds and the use of such compounds for treating various disorders and illnesses alleviated by inhibiting dopamine reuptake, or preventing or delaying the progression of those disorders and illnesses.
  • stereoisomers including enantiomers and diastereomers, which are usually named according to the Cahn-Ingold-Prelog system. It is intended to include all possible stereoisomers, which may be racemic mixtures or other mixtures of R and S stereoisomers (scalemic mixtures which are mixtures of unequal amounts of enantiomers), as well as resolved, substantially pure optically active forms, and pharmaceutically acceptable salts thereof.
  • Stereoisomers of the compounds above can be selectively synthesized or separated into pure, optically-active form using conventional procedures known to those skilled in the art of organic synthesis.
  • mixtures of stereoisomers may be separated by standard techniques including, but not limited to, resolution of racemic forms, normal, reverse-phase, and chiral chromatography, preferential salt formation, recrystallization, and the like, or by chiral synthesis either from chiral starting materials or by deliberate synthesis of target chiral centers.
  • alkyl refers to saturated straight and branched chain hydrocarbon radicals, having 1-6 and preferably 1-4 carbon atoms.
  • alkenyl is used to refer to unsaturated straight and branched chain hydrocarbon radicals including at least one double bond, and having 2-7 and preferably 2-5 carbon atoms. Such alkenyl radicals may be in trans(E) or cis(Z) structural configurations.
  • alkynyl is used herein to refer to both straight and branched unsaturated hydrocarbon radicals including at least one triple bond and having 2-7 and preferably 2-5 carbon atoms.
  • cycloalkyl refers to a saturated cyclic hydrocarbon radical with one or more rings, having 3-14 and preferably 5 or 6-10 carbon ring-atoms.
  • Any alkyl, alkenyl, alkynyl or cycloalkyl moiety of a compound described herein may be substituted with one or more groups, such as halogen, OH, SH, NH 2 , C 1 -C 4 monoalkylamino, C 1 -C 4 dialkylamino, COOH, CN, NO 2 , C 1 -C 4 alkyl or C 1 -C 4 alkoxy.
  • groups such as halogen, OH, SH, NH 2 , C 1 -C 4 monoalkylamino, C 1 -C 4 dialkylamino, COOH, CN, NO 2 , C 1 -C 4 alkyl or C 1 -C 4 alkoxy.
  • aryl refers to an aromatic hydrocarbon radical composed of one or more rings and having 5 or 6-14 carbon atoms and preferably 5 or 6-10 carbon atoms, such as phenyl, naphtnyl, biphenyl, fluorenyl, indanyl, or the like. Any aryl moiety of a compound described herein may be substituted with one or more groups, such as halogen, OH, SH, NH 2 , C 1 -C 4 monoalkylamino, C 1 -C 4 dialkylamino, COOH, CN, NO 2 , C1-C4 alkyl or C1-C4 alkoxy. The aryl moiety is preferably substituted or unsubstituted phenyl.
  • arylalkyl or “aralkyl” as used herein refers to radicals having 6 to 20 carbon atoms that combine both an aryl and an alkyl group, as defined above. Any aralkyl moiety of a compound described herein may optionally be substituted with one or more of the same substituent groups mentioned above in reference to the aryl radical.
  • halogen or "halo" as used herein refers to Fl, Cl, Br and I.
  • alkoxy refers to alkyl-O-, in which alkyl is as defined above.
  • alkylthio refers to alkyl-S-, in which alkyl is as defined above.
  • salts refers to salts derived from non-toxic physiologically compatible acids and bases, which may be either inorganic or organic.
  • useful salts may be formed from physiologically compatible organic and inorganic bases, including, without limitation, alkali and alkaline earth metal salts, e.g., Na, Li, K, Ca, Mg, as well as ammonium salts, and salts of organic amines, e.g., ammonium, trimethylammonium, diethylammonium, and tris-(hydroxymethyl)methylammonium salts.
  • the compounds of the invention also form salts with organic and inorganic acids, including, without limitation, acetic, ascorbic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, salicyclic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methane sulfonic, naphthalene sulfonic, benzene sulfonic, toluene sulfonic and similar known, physiologically compatible acids.
  • zwitterions when a compound contains both a basic moiety and an acidic moiety, zwitterions (“inner salts”) may be formed and are included within the term "salt(s)" as used herein.
  • R 1 -R 6 are as follows wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 , independently of one another, are radicals selected from H, C 1 -C 6 alkyl, OH, halogen, C 5 -C 14 aryl, C 6 -C 20 aralkyl, C 1 -C 6 alkylthio, C 1 -C 6 alkoxy, SH, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, CN, NO 2 carboxy, carbalkoxy, carboxamido, alkylsulfonyl, alkylsulfonyloxy, aminosulfinyl, monoalkyl
  • the expression "method of treating disease alleviated by inhibiting DAT” refers to a treatment using one or more of the compounds described above, which provides relief either by freeing the recipient of a disease or condition mediated by DAT or easing the symptoms or effects of such disease or condition.
  • the method of the invention is intended for treating, preventing, managing and/or delaying the progression of the following: pulmonary conditions such as lung edema; ischemia-reperfusion injury; cardiac conditions, such as acute decompensated heart failure and the cardiorenal syndrome; hyperprolactinaemia (BrE), hyperprolactinemia (AmE) and microprolactinoma; pain including chronic or neuropathic pain; catatonic, dyskinesia, restles legs syndrome and related movement disorders; stress, chronic posttraumatic stress disorder, anxiety disorders, obsessive-compulsive disorders, postpartum depression; schizophrenia, manic, bipolar, and affective disorder; executive function disorders, such as ADHD, Tourette syndrome and autism; cocaine, amphetamine, alcohol dependency, and addictive behavior, such as pathological gambling; neuroendocrinal regulatory disorders; inflammatory conditions, autoimmune diseases and rheumatism; neoplastic disorders, such as pituitary carcinomas, macroprolactinomas; visual sensory disorders, color deficiency
  • the compounds of the invention can be administered to achieve specific dopamine reuptake inhibition by using any acceptable means known in the art, either alone or in combination with one or more other therapeutic agent.
  • the active agent(s) can be administered enterally, parenterally, such as by intravenous infusion, intramuscular, intraperitoneal or subcutaneous injection, by liposome-mediated delivery, vaginally, by inhalation or insufflation, transdermally or by otic delivery.
  • a daily dose of the compound of the invention in the range from about 0.01 mg to about 200 mg/kg of body weight can be administered.
  • a daily dose of from 0.1 to 100, and preferably from 1 to 30 mg/kg per day in one or more applications per day should be effective to produce the desired result.
  • a suitable dose for oral administration would be in the range of 1-30 mg/kg of body weight per day, whereas a typical dose for intravenous administration would be in the range of 1-10 mg/kg of body weight per day.
  • the dosage actually administered will depend upon the condition being treated, the gender, age, health and weight of the recipient, the type of concurrent treatment, if any, and the frequency of treatment.
  • the effective dosage amount may be determined by one skilled in the art on the basis of routine empirical activity testing to measure the bioactivity of the compound(s) in a bioassay, and thus establish the appropriate dosage to be administered.
  • the compounds of the invention will typically be administered from 1-4 times a day, so as to deliver the above-mentioned daily dosage.
  • the exact regimen for administration of the compounds and compositions described herein will necessarily be dependent on the needs of the individual subject being treated, the type of treatment administered and the judgment of the attending medical specialist.
  • the term "subject" includes both humans and animals.
  • the compounds of the invention may be administered as such, or in a form from which the active agent can be derived, such as a prodrug.
  • a prodrug is a derivative of a compound described herein, the pharmacologic action of which results from the conversion by chemical or metabolic processes in vivo to the active compound.
  • Prodrugs include, without limitation, ester derivatives of the compounds of formula I, above.
  • Other prodrugs may be prepared according to procedures well known in the field of medicinal chemistry and pharmaceutical formulation science. See, e.g., Lombaert et al., J. Med. Chem., 37: 498-511 (1994 ); and Vepsalainen, Tet. Letters, 40: 8491-8493 (1999 ).
  • the DAT specific compounds described herein and the pharmaceutically acceptable salts thereof are preferably formulated in unit dosage form for ease of administration and uniformity of dosage.
  • unit dosage form refers to a physically discrete unit of the active agent appropriate for the subject to be treated. Each dose should contain the quantity of active ingredient calculated to produce the desired therapeutic effect, either as such, or in association with the selected pharmaceutical carrier medium and/or supplemental active agent(s), if any.
  • the DAT inhibitory compounds of the invention will be administered in dosage form containing from about 0.01 mg to about 200 mg of the active ingredient, with a range of about 30 mg to about 100 mg being preferred.
  • the orally administered dosage unit may be in the form of tablets, caplets, dragees, pills, semisolids, soft or hard gelatin capsules, aqueous or oily solutions, emulsions, suspensions or syrups.
  • Suitable dosage forms for parenteral administration include injectable solutions or suspensions, suppositories, powder formulations, such as microcrystals or aerosol spray.
  • the active agent may also be incorporated into a conventional transdermal delivery system.
  • a pharmaceutical composition in accordance with the present invention comprises one or more of the compounds above, in combination or admixture with a pharmaceutically acceptable carrier medium.
  • the composition may, if desired, be administered in conjunction with one or more supplemental active agents.
  • the DAT inhibiting agent may be used in combination with L-dopa for the treatment of Parkinson's disease; or in combination with a selective serotonin reuptake inhibitor (SSRI) for the treatment of depression and or cocaine abuse and addiction; or in combination with dopamine D2 antagonist for the treatment of schizophrenia; or in combination with cholinergic modulators for the treatment of Alzheimer disease or other diseases or conditions in which patients have a cognitive deficit.
  • the compound(s) of the invention may be administered either simultaneously (e.g., in the same formulation or not) or sequentially with the supplemental therapeutic agent(s).
  • the expression "pharmaceutically acceptable carrier medium” includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface agent agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, fillers and the like as suited for the particular dosage form desired.
  • any conventional pharmaceutical carrier medium is incompatible with the DAT inhibitor compounds of the present invention, such as by producing an undesirable biological effect or otherwise interacting in an deleterious manner with any other component(s) of a formulation comprising such compounds, its use is contemplated to be within the scope of this invention.
  • the therapeutic agent may be mixed with pharmaceutically inert, inorganic or organic excipients, such as lactose, sucrose, glucose, gelatine, malt, silica gel, starch or derivatives thereof, talc, stearic acid or its salts, dried skim milk, vegetable, petroleum, animal or synthetic oils, wax, fat, polyols, and the like.
  • pharmaceutically inert, inorganic or organic excipients such as lactose, sucrose, glucose, gelatine, malt, silica gel, starch or derivatives thereof, talc, stearic acid or its salts, dried skim milk, vegetable, petroleum, animal or synthetic oils, wax, fat, polyols, and the like.
  • excipients such as water, alcohols, aqueous saline, aqueous dextrose, polyols, glycerine, lipids, phospholipids, cyclodextrins, vegetable, petroleum, animal or synthetic oils.
  • excipients such as vegetable, petroleum, animal or synthetic oils, wax; fat and polyols.
  • compressed gases suitable for this purpose such as oxygen, nitrogen and carbon dioxide.
  • the pharmaceutical composition or formulation may also contain one or more additives including, without limitation, preservatives, stabilizers, e.g., UV stabilizers, emulsifiers, sweeteners, salts to adjust the osmotic pressure, buffers, coating materials and antioxidants.
  • additives including, without limitation, preservatives, stabilizers, e.g., UV stabilizers, emulsifiers, sweeteners, salts to adjust the osmotic pressure, buffers, coating materials and antioxidants.
  • the present invention further provides controlled-release or sustained-release therapeutic dosage forms for the pharmaceutical composition, in which the composition is incorporated into a delivery system.
  • This dosage form controls release of the active agent(s) in such a manner that an effective concentration of the active agent(s) in the bloodstream can be maintained over an extended period of time, with the concentration in the blood remaining relatively constant, to improve therapeutic results and/or minimize side effects.
  • a controlled-release system would provide minimum peak to trough fluctuations in blood plasma levels of the active agent.
  • the active agent(s) may be present in an amount of at least 0.5 and generally not more than 95% by weight, based on the total weight of the composition, including carrier medium and/or supplemental active agent(s), if any.
  • the proportion of active agent(s) varies between 30-90% by weight of the composition.
  • 1.2 ml 7.5N aq. HCl was stirred (at 0°C) into a mixture of 0.94 g benzyl amine and 0.58g of potassium cyanide in 2ml of water. 0.7g formaldehyde was then added dropwise into the mixture. The resulting mixture was stirred at room temperature for 2 hours and then cooled to 0°C. A solution of 0.62g sodium nitrite in 1ml water was added slowly dropwise to the mixture followed by the addition of 1.2ml 7.5N HCl aq. solution while cooling. The mixture was stirred at room temperature for 1 hour. Ether was used to extract the resulting mixture three times. The combined ether solution was dried with anhydrous sodium sulfate.
  • N-phenylcarbamoyl-3-(p-carboxylbenzyl-syndonimine (2); N-phenylcarbamoyl-3-( p -methyl-benzyl)-sydnonimine (3); N-(3',4'-dichlorophenyl) carbamoyl-3-phenethyl sydnonimine (4); N-(3',4'-dinitrophenyl) carbamoyl-3-p-nitrophenethyl sydnonimine (5); N-phenylcarbamoyl-3-(phenylpropyl)-sydnonimine (6); and N-phenylcarbamoyl-3-( p -fluoro-benzyl)-sydnonimine (7) were synthesized following essentially the same procedure as described in Example 1, above, with appropriate substitution of different starting materials in equivalent amounts.
  • hrNET Receptor Biology
  • Preferred compounds of the invention have a DAT binding inhibition (at 10 ⁇ m) of greater than or equal to 90% and a NET binding inhibition (at 10 ⁇ M) of less than or equal to 15%; or a ratio of DAT:NET binding inhibition (at 10 ⁇ M) of at least 9:1.
  • Example 9 The following materials and methods are provided to facilitate the practice of Example 9, in which drug concentration in certain biological samples were assessed using different routes of administration. Parameters used in dosing and drug administration of the compound of Example 3: Dose route Dose range Dose volume (Use a 1-ml syringe with appropriate oral feeding needle.) i.v. 10mg/kg 5 -10 x bodyweight (5-10 ml/ kg, i.e. a 25g mouse receives 125 - 250ul) i.p 10mg/kg 10 x bodyweight Oral 10,30mg/kg 10 x bodyweight
  • mice per time point. If all three routes are conducted in same day, one group of pre- dose is efficient.
  • a dose response study was conducted of locomotor depression induced by the compound of Example 3, according to NIDA's Medication Development Division (MDD) locomoter activity studies standard protocol. The study was conducted using 40 Digiscan locomotor activity testing chambers (40.5 X 40.5 X 30.5 cm) housed in sets of two, within sound attenuating chambers. A panel of infrared beams (16 beams) and corresponding photodetectors were located in the horizontal direction along the sides of each activity chamber. A 7.5 W incandescent light above each chamber provided dim illumination. Fans provided an 80dB ambient noise level within the chamber.
  • MDD Medication Development Division
  • mice 8 non-habituated male Swiss Webster mice (Hsd:ND4, aged 2-3 months) were injected via the intraperitoneal (IP) route with either vehicle (2% methyl cellulose) or the compound of Example 3, above, (3, 10, 30 or 100 mg/kg) twenty minutes prior to locomotor activity testing. Just piro to placement in the apparatus, all mice received a saline injection IP. In all studies, horizontal activity (interruption of photocell beams) was measured for 1 hour within 10 minute periods. Testing was conducted with one mouse per activity chamber.
  • IP intraperitoneal
  • a time course/dose response study of the locomotor depression inducing effect of the compound of Example 3 was conducted, according to the same MDD locomotor activity studies time course protocol described immediately above, except that groups of 8 mice were injected with either vehicle (2% methylcellulose) or the compound of Example 3 (3, 10, 30 or 100 mg/kg), immediately prior to locomotor activity testing. Behavioral observations were recorded on each mouse at 30, 120 and 480 minutes following 100 mg/kg of the test compound. The vehicle used in this study was 2% methylcellulose.
  • the inventors have identified DAT selective inhibitors for use in the treatment and prevention of cocaine abuse and other disorders associated with aberrant dopamine reuptake.
  • Two such inhibitors namely, the compounds of Examples 3 and 6, above, are well tolerated up to at least 200 mg/kg. Observable changes in behavior occurred in minutes and lasted for about 2-3 hours. Notably subjects treated with the compound of Example 3 became lethargic at dosages above 125 kg/mg, whereas this effect was reduced at higher concentrations of the compound of Example 6.
  • Figure 6A shows average horizontal activity counts/10 min as a function of time (0-8 hr) and dose of the compound (top to bottom panels). Treatment with this compound resulted in time- and dose-dependent depression of locomotor activity following 30 and 100 mg/kg. Depressant effects of 30 and 100 mg/kg occurred within 10 minutes following injection and lasted 140 to 160 minutes. The period 20-50 min was selected for analysis of dose-response data because this was the time period in which maximal suppression first appeared as a function of dose.
  • the mean average horizontal activity counts/10 min for this 30-min period were fit to a linear functionof log 10 dose of the descending portion of the dose-effect curve (3 to 100 mg/kg dose range).
  • FIG. 6B shows average horizontal activity counts/10 min as a function of time (0-8 hr) and dose of the test compound (top to bottom panels).
  • Treatment with this compound resulted in time-dependent depression of locomotor activity following 100 mg/kg.
  • Depressant effects of 100 mg/kg occurred within 10 minutes following injection and lasted 160 minutes.
  • the period 50-80 min was selected for analysis of dose-response data because this was the time period in which maximal suppression first appeared as a function of dose.
  • the mean average horizontal activity counts/10 min for this 30-min period were fit to a linear function of log 10 dose of the descending portion of the dose-effect curve (10 to 100 mg/kg dose range).
  • the Irwin test equipment timer, viewing jar and support, open arena, grid, ruler, sound box, wood stocks, kimwipes box
  • Open Field testing was also performed. In carrying out this testing, individually housed male and female mice aged 8-12 weeks were used. The mice were maintained on a reverse L:D/12 p.m.: 12 a.m. cycle in a barrier facility. Food and water were available ad libitum. Testing occurred towards the end of the light cycle between 6-12 a.m. Mice were acclimated to the testing room for at least 30 minutes. The assay was performed in a custom-made Open Field Apparatus. Each chamber was a 50 by 50 cm square. The experiment was recorded and tracked by a tracking system obtained from Viewpoint.
  • the time and the path length in the center of the open field were determined.
  • the center of the open field is defined as a 13.5 x 13.5 cm square in the geometric center of the arena.
  • the percent of path in the center is calculated as Path length in the center Total path length ⁇ 100 %
  • the total path length and path length for 60 minutes at 5 minute intervals was determined as a measure of locomotor activity.
  • feces produced by each experimental animal during the test was counted. Each chamber was cleaned between individual mouse testing.
  • Novel environment-induced feeding suppression (NEIFS) testing was also performed. Individually housed male mice aged 8-12 weeks are used for this testing. Mice were maintained no a reverse L:D/ 12 p.m.: 12a.m. cycle in a barrier facility with food and water available ad libitum. Testing occurred towards the end of the light cycle between 6-12 a.m. The mice were acclimated to the testing room for at least 30 minutes.
  • the compound of Example 3 induced measurable anxiolytic effects. See Figure 10 . Notably, the compound had no effect on the number of fecal boli in open field testing.
  • Rotarod assays were also performed using the experimental protocol and design set forth below. Individually housed male mice aged 8-12 weeks were used for this experiment. Mice were maintained on a reverse L:D/ 12 p.m.: 12 a.m. cycle in a barrier facility with food and water available ad libitum. Testing occurred towards the end of the light cycle between 6-12 a.m. Mice were acclimated to the testing room for at least 30 minutes.
  • mice were given 10 trials with the maximum duration of 3 minute and a 30-second intertrial interral (ITI). Each mouse was placed on the EZRod machines and the latency to fall was recorded for all trials. If the mouse fell or 3 minutes elapsed, the mouse was left in the bottom of the EzRod test chamber for 30 seconds before starting the next trial.
  • ITI intertrial interral
  • the latency to fall was compared between the two groups by analysis of variance (ANOVA) with repeated measures.

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Claims (16)

  1. Verbindung zur Verwendung in einem Verfahren zur Behandlung oder Verzögerung der Progression von Störungen, die durch Hemmung der Dopamin-Wiederaufnahme in einem Patienten gemindert werden, worin das Verfahren das Verabreichen einer therapeutisch wirksamen Menge von zumindest einer Verbindung umfasst, die aus der aus N-Phenylcarbamoyl-3-(p-methylbenzyl)sydnonimin und N-Phenylcarbamoyl-3-(phenylpropyl)sydnonimin bestehenden Gruppe ausgewählt ist; und pharmazeutisch annehmbare Salze der Verbindung.
  2. Verwendung einer Verbindung zur Herstellung eines Medikaments zur Behandlung oder Verzögerung der Progression von Störungen, die durch Hemmung der Dopamin-Wiederaufnahme in einem Patienten gemindert werden, worin die Verbindung aus der aus N-Phenylcarbamoyl-3-(p-methylbenzyl)sydnonimin und N-phenylcarbamoyl-3-(phenylpropyl)sydnonimin bestehenden Gruppe ausgewählt ist; und pharmazeutisch annehmbarer Salze der Verbindung.
  3. Verbindung zur Verwendung in einem Behandlungsverfahren nach Anspruch 1 oder Verwendung nach Anspruch 2, worin der Leidens- oder Krankheitszustand aus der aus Folgendem bestehenden Gruppe ausgewählt ist: Lungenleiden; Ischämie-Reperfusionsschaden; Herzleiden; Hyperprolaktinämie (BrE) oder Hyperprolaktinämie (AmE) und Mikroprolaktinom; Schmerzen; Bewegungsstörungen; Stress, chronische posttraumatische Belastungsstörung, Angststörungen, Zwangsstörungen, postpartale Depression; Schizophrenie, manische, bipolare und affektive Störung; Ausführungsfunktionsstörungen; Kokainabhängigkeit, Amphetaminabhängigkeit, Alkoholabhängigkeit, Suchtverhalten; neuroendokrine Regulationsstörungen; inflammatorische Leiden, Autoimmunkrankheiten und Rheumatismus; neoplastische Störungen; visuelle Wahrnehmungsstörungen, Farbfehlsichtigkeit; und Ejakulations- und damit zusammenhängende sexuelle Funktionsstörung.
  4. Verbindung zur Verwendung in einem Behandlungsverfahren nach Anspruch 1 oder Verwendung nach Anspruch 2, worin die verabreichte Verbindung N-Phenyl-carbamoyl-3-(phenylpropyl)sydnonimin ist.
  5. Verbindung zur Verwendung in einem Behandlungsverfahren oder Verwendung nach einem der Ansprüche 1 bis 4, worin:
    (a) die zumindest eine Verbindung, gegebenenfalls in Verbindung mit zumindest einem weiteren Therapeutikum, zur Behandlung von Kokainabhängigkeit, Aufmerksamkeitsdefizitstörung, Depression, Schizophrenie, Narkolepsie, Adipositas oder Parkinson-Krankheit verabreicht wird; oder
    (b) die Verbindung und das optionale weitere Therapeutikum zur Behandlung von Kokainabhängigkeit verabreicht werden; oder
    (c) die Verbindung und das optionale weitere Therapeutikum zur Behandlung einer Aufmerksamkeitsdefizitstörung verabreicht werden.
  6. Verbindung zur Verwendung in einem Behandlungsverfahren oder Verwendung nach einem der Ansprüche 1 bis 5, worin die Verbindung in Einzeldosierungsform verabreicht wird, wobei die Dosierungseinheit 0,01 bis 200 mg der Verbindung pro Kilogramm Körpergewicht des Patienten pro Tag enthält.
  7. Verbindung zur Verwendung in einem Behandlungsverfahren oder Verwendung nach Anspruch 6, worin die Dosierungseinheit ein pharmazeutisch annehmbares Vehikel umfasst.
  8. Verbindung zur Verwendung in einem Behandlungsverfahren oder zur Verwendung nach einem der Ansprüche 1 bis 7, worin die Verbindung oral oder parenteral verabreicht wird.
  9. Verbindung zur Verwendung in einem Behandlungsverfahren oder Verwendung nach einem der Ansprüche 1 bis 8, worin die zumindest eine Verbindung in Verbindung mit zumindest einem zusätzlichen Therapeutikum entweder simultan oder nacheinander verabreicht wird, das aus der aus Folgendem bestehenden Gruppe ausgewählt ist: L-dopa zur Behandlung der Parkinson-Krankheit; ein selektiver Serotonin-Wiederaufnahmehemmer zur Behandlung von Depression und/oder Kokainmissbrauch und -abhängigkeit; ein Dopamin-D2-Antagonist zur Behandlung von Schizophrenie; und ein cholinerger Modulator zur Behandlung der Alzheimer-Krankheit oder anderer Krankheiten oder Leiden, bei denen Patienten ein kognitives Defizit aufweisen.
  10. Verbindung, die aus der aus N-Phenylcarbamoyl-3-(p-methylbenzyl)sydnonimin und N-Phenylcarbamoyl-3-(phenylpropyl)sydnonimin bestehenden Gruppe ausgewählt ist; und pharmazeutisch annehmbare Salze der Verbindung.
  11. Verbindung nach Anspruch 10, worin die Verbindung N-Phenylcarbamoyl-3-(phenylpropyl)sydnonimin ist.
  12. Pharmazeutische Zusammensetzung zur Behandlung oder Verzögerung der Progression von Störungen, die durch Hemmung der Dopamin-Wiederaufnahme gemindert werden, wobei die Zusammensetzung eine Verbindung nach Anspruch 10 oder Anspruch11 und ein pharmazeutisch annehmbares Vehikel umfasst.
  13. Zusammensetzung nach Anspruch 12, worin:
    (a) die Zusammensetzung in fester Form vorliegt und auch einen pharmazeutisch annehmbaren Exzipienten umfasst; oder
    (b) die Zusammensetzung in flüssiger Form vorliegt und auch einen pharmazeutisch annehmbaren Verdünner umfasst; oder
    (c) die Zusammensetzung in Einzeldosierungsform vorliegt; und/oder
    (d) die Zusammensetzung ferner zumindest einen selektiven Serotonin-Wiederaufnahmehemmer umfasst.
  14. Pharmazeutische Zusammensetzung nach Anspruch 13(c) in Einzeldosierungsform.
  15. Verbindung zur Verwendung in einem Verfahren zur Behandlung eines Leidens- oder Krankheitszustands, der durch Modulieren der Dopamin-Wiederaufnahmeaktivität und dadurch Erhöhen der dopaminergen Funktionen gemindert wird, worin das Verfahren das Verabreichen einer therapeutisch wirksamen Menge von zumindest einer Verbindung, die aus der aus N-Phenylcarbamoyl-3-(p-methylbenzyl)-sydnonimin und N-Phenylcarbamoyl-3-(phenylpropyl)sydnonimin bestehenden Gruppe ausgewählt ist, an einen den Leidens- oder Krankheitszustand aufweisenden Patienten umfasst; und pharmazeutisch annehmbare Salze der Verbindung.
  16. Verwendung einer Verbindung zur Herstellung eines Medikaments zur Behandlung eines Leidens- oder Krankheitszustands, der durch Modulieren der Dopamin-Wiederaufnahmeaktivität und dadurch Erhöhen der dopaminergen Funktionen gemindert wird, worin die Verbindung aus der aus N-Phenylcarbamoyl-3-(p-methylbenzyl)sydnonimin und N-Phenylcarbamoyl-3-(phenylpropyl)sydnonimin bestehenden Gruppe ausgewählt ist; und pharmazeutisch annehmbarer Salze der Verbindung.
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